Significance Aberrant growth patterns have been shown to be correlated with a more rapid disease course and decreased survival in HIV-infected infants. Evidence in human and nonhuman primates has shown that the insulin-like growth factor (IGF) system plays a central role in the growth restriction, failure-to-thrive, and wasting associated with HIV/SIV infection. Objectives Previous studies have shown that direct administration of IGF-I to normally grown fetal monkeys has somatic, growth, and immune system effects, and that treatment of SIV-infected fetuses in utero with IGF-I enhances survival. Our goal was to explore a combined treatment approach by administering IGF-I to SIV-infected fetuses and infants with a potent antiretroviral which has been shown to substantially diminish viral load. Results Fetuses were directly infected with pathogenic SIV during the early second trimester and the dams administered PMPA beginning approximately 4 weeks post-fetal infection (once daily 10 mg/kg). IGF-I (80 5g/kg) was directly administered to SIV-infected fetuses intraperitoneal via ultrasound-guidance (gestational day 110-120, 130-140, 150-155; every other day). Newborns were delivered at term and treatment with PMPA (10 mg/kg once daily) and IGF-I was initiated. Results of these studies have shown improvements in growth and immune parameters with combined treatment, and increased serum circulating concentrations of IGF-I when compared to SIV-infected infants without IGF administration. However, enhanced postnatal growth rates were transitory, even with continued IGF administration. These studies have shown that although IGF-I may enhance growth and survival in utero, effects postnatally were limited. Future Directions Studies currently in progress focus on IGF tissue expression and the activation state of skeletal muscle IGF-receptor with and without SIV-infection and IGF-I administration. KEY WORDS SIV, fetal growth, IGF-I, growth restriction, fetal therapy, antiretrovirals FUNDING NIH Grants DK49317 and RR00169